The genetic landscape of breast carcinomas with neuroendocrine differentiation

Caterina Marchiò, Felipe C. Geyer, Charlotte K Y Ng, Salvatore Piscuoglio, Maria R. De Filippo, Marco Cupo, Anne M. Schultheis, Raymond S. Lim, Kathleen A. Burke, Elena Guerini-Rocco, Mauro Papotti, Larry Norton, Anna Sapino, Britta Weigelt, Jorge S. Reis-Filho

Research output: Contribution to journalArticlepeer-review


Neuroendocrine breast carcinomas (NBCs) account for 2–5% of all invasive breast cancers, and are histologically similar to neuroendocrine tumours from other sites. They typically express oestrogen receptor (ER), and are HER2-negative and of luminal 'intrinsic' subtype. Here, we sought to define the mutational profile of NBCs, and to investigate whether NBCs and common forms of luminal (ER+/HER2) breast carcinoma show distinct repertoires of somatic mutations. Eighteen ER+/HER2 NBCs, defined as harbouring >50% of tumour cells expressing chromogranin A and/or synaptophysin, and matched normal tissues were microdissected and subjected to massively parallel sequencing targeting all exons of 254 genes most frequently mutated in breast carcinomas and/or related to DNA repair. Their mutational repertoire was compared with that of ER+/HER2 breast carcinomas (n = 240), PAM50-defined luminal breast carcinomas (luminal A, n = 209; luminal B, n = 111) and invasive lobular carcinomas (n = 127) from The Cancer Genome Atlas. NBCs were found to harbour a median of 4.5 (range 1–11) somatic mutations, similar to that of luminal B breast carcinomas (median = 3, range 0–17) but significantly higher than that of luminal A breast carcinomas (median = 3, range 0–18, p = 0.02). The most frequently mutated genes were GATA3, FOXA1, TBX3, and ARID1A (3/18, 17%), and PIK3CA, AKT1, and CDH1 (2/18, 11%). NBCs less frequently harboured PIK3CA mutations than common forms of ER+/HER2, luminal A and invasive lobular carcinomas (p < 0.05), and showed a significantly higher frequency of somatic mutations affecting ARID1A (17% versus 2%, p < 0.05) and the transcription factor-encoding genes FOXA1 (17% versus 2%, p = 0.01) and TBX3 (17% versus 3%, p < 0.05) than common-type ER+/HER2 breast carcinomas. No TP53 somatic mutations were detected in NBCs. As compared with common forms of luminal breast carcinomas, NBCs show a distinctive repertoire of somatic mutations featuring lower frequencies of TP53 and PIK3CA mutations, enrichment for FOXA1 and TBX3 mutations, and, akin to neuroendocrine tumours from other sites, ARID1A mutations.

Original languageEnglish
Pages (from-to)405-419
Number of pages15
JournalJournal of Pathology
Issue number3
Publication statusPublished - Feb 1 2017


  • breast carcinoma
  • chromogranin A
  • copy number alterations
  • massively parallel sequencing
  • neuroendocrine differentiation
  • somatic mutations
  • synaptophysin

ASJC Scopus subject areas

  • Pathology and Forensic Medicine


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